The present invention is related to benzothiazole compounds, and more particularly to benzothiazole dervitives showing activity as adenosine receptor ligands.
Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzym A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
The receptors for adenosine have been classified as A1, A2A, A2B and A3 receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtyps has been classically characterised by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The A1 and A3 receptors, coupled with Gi proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A2A and A2B receptors couple to Gs proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A1 receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A3 subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.
The A1 receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A2A receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) was cloned from human and mouse with 45% homology of human A2B with human A1 and A2A receptors. The A3 receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
The A1 and A2A receptor subtypes are proposed to play complementary roles in adenosine""s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A1) or increase the oxygen supply (A2A) and so reinstate the balance of energy supply: demand within the tissue. The actions of both subtyps is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.
Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A3 receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A3 receptor plays a role in mediating asthmatic attacks and other allergic responses.
Adenosine is also a neuromodulator, possessing global importance in the modulation of molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A1 agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A2a-antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer""s disease and are useful as neuroprotective agents. Adenosine A2a-receptor antagonists inhibit the release of dopamine from central synaptic terminals and stimulate locomotor activity and consequently improve Parkinsonian symptoms. The central activities of adenosine are also implicated in the molecular mechanism underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and substance abuse. Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants and antidepressants, and they may be used in the treatment of ADHD (attention deficit hyper-activity disorder).
An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus have potential as cardioprotective agents.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds, which antagonise the renal affects of adenosine, have potential as renal protective agents. Furthermore, adenosine A3 and/or A2B antagonists may be useful in the treatment of asthma and other allergic responsesor and in the treament of diabetes mellitus and obesity.
Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:
Bioorganic and Medicinal Chemistry, 6, (1998), 619-641,
Bioorganic and Medicinal Chemistry, 6, (1998), 707-719,
J. Med. Chem., (1998), 41, 2835-2845,
J. Med. Chem., (1998), 41, 3186-3201,
J. Med. Chem., (1998), 41, 2126-2133,
J. Med. Chem., (1999), 42, 706-721,
J. Med. Chem., (1996), 39, 1164-1171,
Arch. Pharm. Med. Chem., 332, 39-41, (1999).
The present invention is a method of treatment of a person having a disease state treatable by modulation of the adenosine A2a receptor by administering to a person in need of such treatment an effective amount of a compound of the formula 
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy;
R2, R3 are independently from each other hydrogen, halogen, lower alkyl or lower alkyloxy;
R4 is hydrogen, lower alkyl, lower alkenyl, halogen, xe2x80x94C(O)OH, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)-halogen-lower alkyl, xe2x80x94CH(OH)-halogen-lower alkyl, xe2x80x94C(O)O-lower alkyl, xe2x80x94NHC(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94OH,
or is phenyl, which is optionally attached to the benzo group via the linker xe2x80x94(O)mxe2x80x94(CH2)nxe2x80x94 and is unsubstituted or substituted by N(R5)(R6), halogen, alkoxy or nitro,
or is 2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is a five or six membered aromatic or non aromatic heterocycle, which may be attached to the benzo group via the linker xe2x80x94(O)mxe2x80x94(CH2)n or xe2x80x94Nxe2x95x90C(CH3)xe2x80x94 and is unsubstituted or substituted by one or two group(s) R7, wherein R7 is defined below;
R is
(a) phenyl, unsubstituted or substituted by lower alkyl, halogen-lower alkyl, lower alkoxy, cyano, nitro, xe2x80x94C(O)H, xe2x80x94C(O)OH or by the following groups
xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94N(R5)xe2x80x94(CH2)o-lower alkoxy,
xe2x80x94(CH2)nO-halogen-lower alkyl,
xe2x80x94(CH2)nOxe2x80x94(CH2)n+1xe2x80x94O-lower alkyl,
xe2x80x94S(O)2xe2x80x94N(R5)xe2x80x94(CH2)nxe2x80x94O-lower alkyl,
xe2x80x94(CH2)nxe2x80x94OR5,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-lower alkoxy,
xe2x80x94(CH2)nN[(CH2)o-lower alkoxy]2,
xe2x80x94(CH2)nN(R5)(R6),
xe2x80x94(CH2)nN[S(O)2CH3]2,
xe2x80x94(CH2)nN[R5][S(O)2CH3],
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oNR5R6,
xe2x80x94(CH2)nN(R5)-lower alkenyl,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-cycloalkyl,
xe2x80x94(CH2)nN(R5)xe2x80x94C(O)O-lower alkyl,
xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94N(R5)(R6),
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94S-lower alkyl,
xe2x80x94S(O)2xe2x80x94N(R5)(R6),
xe2x80x94(CH2)nN(R5)xe2x80x94S(O)2CH3 
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-phenyl,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94OH,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94CH(OH)xe2x80x94CF3,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94CF3,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94Oxe2x80x94CH(OH)xe2x80x94C6H3(OCH3)2,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94Oxe2x80x94C(O)xe2x80x94C6H3(OCH3)2,
xe2x80x94N(R5)xe2x80x94C(O)-morpholin,
xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94N(R5)-phenyl, substituted by alkoxy,
xe2x80x94S(O)2-morpholin,
or is phenyl, which is unsubstituted or substituted by
xe2x80x94(CR5R6)nxe2x80x94 five to seven membered aromatic or non aromatic heterocycle, and wherein the heterocycle is unsubstsituted or substituted by hydroxy, xe2x80x94N(R5)(R6), lower alkoxy or lower alkyl, or by xe2x80x94(CH2)nN(R5)(CH2)oxe2x80x94 five or six membered aromatic or non aromatic heterocycle and wherein the heterocycle is unsubstituted or substituted by hydroxy, xe2x80x94N(R5)(R6) or lower alkyl, or is
b) xe2x80x94(CH2)nxe2x80x94 five or six membered aromatic or non aromatic heterocycle, with the exception of the the piperazinyl group in case if n=0, which rings are unsubstituted or substituted by one or two substituents, selected from the group consisting of 2-oxo-pyrrolidin, piperidinyl, phenyl, xe2x80x94(CH2)nOH, halogen, CF3, xe2x95x90O, lower alkyl, cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nNH2, xe2x80x94(CH2)nCN, xe2x80x94C(O)O-lower alkyl, xe2x80x94CH2xe2x80x94Oxe2x80x94S(O)2CH3, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)xe2x80x94(CH2)n-lower alkoxy, xe2x80x94CH2xe2x80x94N(R6)C6H4F, xe2x80x94CH2xe2x80x94N(R6)C(O)O-lower alkyl, xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94(CH2)n, xe2x80x94O-lower alkyl, -or by tetrahydrofuran, substituted by 4-Cl-phenyl, or by piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl, or is
c) xe2x80x94(CH2)n+1-phenyl,
xe2x80x94N(R5)(CH2)n-phenyl, unsubstituted or substituted by lower alkoxy,
xe2x80x94O(CH2)n-phenyl, or
xe2x80x94N(R5)C(O)-phenyl, or is
d) xe2x80x94N(R5)(CH2)nxe2x80x94 5-or 6 membered aromatic or non aromatic heterocycle, unsubstituted or substituted by lower alkyl, xe2x80x94(CH2)nxe2x80x94 5-or 6 membered aromatic or non aromatic heterocycle or is
e) xe2x80x94(CH2)nxe2x80x94N(R5)(R6), lower alkyl, xe2x80x94Oxe2x80x94(CH2)n-lower alkoxy, xe2x80x94(CH2)n-lower alkoxy, lower alkoxy, cycloalkyl, xe2x80x94N(R5)(CH2)nO-lower alkyl, xe2x80x94N(R5)(CH2)nOH, xe2x80x94N(R5)(CH2)nN(R5)(R6), xe2x80x94C(O)O-lower alkyl, xe2x80x94(CH2)nOH, xe2x80x94(HCxe2x95x90CH)nC(O)O-lower alkyl, octahydro-quinoline, 3,4-dihydro-1H-isoquinoline, 2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or 1,4-dioxa-8-aza-spiro[4,5]decane;
X is O, S or two hydrogen atoms;
R5, R6 are independently from each other hydrogen or lower alkyl,
R7 is lower alkyl, lower alkoxy, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)O-benzyl, xe2x80x94C(O)O-lower alkyl,
xe2x80x94(CH2)nNR5R6, pyridinyl, unsubstituted or substituted by lower alkyl, or is xe2x80x94CH2N(R5)xe2x80x94C(O)O-lower alkyl, xe2x80x94NHxe2x80x94C(phenyl)3, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, optionally substituted by lower alkyl;
n is 0, 1, 2, 3 or 4;
m is 0 or 1;
is 0, 1, 2, 3 or 4;
and pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of diseases related to the adenosine receptor.
Some minor subgroups of compounds of the present formula I are known compounds and have been described, for example in EP 427 963, U.S. Pat. No. 5,099,021, EP 295 656 or DE 19 531 49. These compounds possess microbicide activity or may be used for lowering the blood glucose level. Furthermore, WO 00/18767 describes 2-piperazino alkylamino benzoazole, having an affinity to the dopamine subtype specific ligands and are therefore useful in the treatment of diseases, related to this receptor. The compounds of WO 00/18767 are not encompassed from the scope of the present invention.
It has surprisingly been found that the compounds of formula I are adenosine receptor ligands.
Objects of the present invention are the use of compounds of formula I or their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the adenosine A2 receptor, novel compounds of formula I-A per se, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer""s disease, Parkinson""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson""s disease as well as ADHD and diabetes mellitus.
The present invention includes novel compounds of the formula 
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy;
R2, R3 are independently from each other hydrogen, halogen, lower alkyl or lower alkyloxy;
R4 is hydrogen, lower alkyl, lower alkenyl, halogen, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)-halogen-lower alkyl, xe2x80x94CH(OH)-halogen-lower alkyl, xe2x80x94C(O)O-lower alkyl, xe2x80x94NHC(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94OH,
or is phenyl, which is optionally attached to the benzo group via the linker xe2x80x94(O)mxe2x80x94(CH2)nxe2x80x94 and is unsubstituted or substituted by N(R5)(R6), halogen or nitro, or is 2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is
a five or six membered aromatic or non aromatic heterocycle, which may be attached to the benzo group via the linker xe2x80x94(O)mxe2x80x94(CH2)n or xe2x80x94Nxe2x95x90C(CH3)xe2x80x94 and is unsubstituted or substituted by one or two group(s) R7, wherein R7 is defined below;
Rxe2x80x2 is
(a) phenyl, optionally unsubstituted or substituted by halogen-lower alkyl, xe2x80x94C(O)H or by the following groups
xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94N(R5)xe2x80x94(CH2)nlower alkoxy,
xe2x80x94(CH2)nO-halogen-lower alkyl,
xe2x80x94(CH2)nOxe2x80x94(CH2)n+1O-lower alkyl,
xe2x80x94S(O)2xe2x80x94N(R5)xe2x80x94(CH2)nO-lower alkyl,
xe2x80x94(CH2)nOR5,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-lower alkoxy,
xe2x80x94(CH2)nN[(CH2)o-lower alkoxy]2,
xe2x80x94(CH2)nN[S(O)2CH3]2,
xe2x80x94(CH2)nN[R5][S(O)2CH3],
xe2x80x94(CH2)nN(R5)-lower alkenyl,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-cycloalkyl,
xe2x80x94(CH2)nN(R5)xe2x80x94C(O)O-lower alkyl,
xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94N(R5)(R6),
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94S-lower alkyl,
xe2x80x94(CH2)nN(R5)xe2x80x94S(O)2CH3 
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)o-phenyl,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oOH,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oCH(OH)xe2x80x94CF3,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94CF3,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94Oxe2x80x94CH(OH)xe2x80x94C6H3(OCH3)2,
xe2x80x94(CH2)nN(R5)xe2x80x94(CH2)oxe2x80x94Oxe2x80x94C(O)xe2x80x94C6H3(OCH3)2,
xe2x80x94N(R5)xe2x80x94C(O)-morpholin,
xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94N(R5)-phenyl, substituted by alkoxy,
xe2x80x94S(O)2-morpholin,
or is phenyl, which is unsubstituted or substituted by
xe2x80x94(CR5R6)nxe2x80x94 five to seven membered aromatic or non aromatic heterocycle, and
wherein the heterocycle is unsubstituted or substituted by hydroxy, xe2x80x94N(R5)(R6) or lower alkyl, or by xe2x80x94(CH2)nN(R5)(CH2)oxe2x80x94 five or six membered aromatic or non aromatic heterocycle and wherein the heterocycle is unsubstituted or substituted by hydroxy,
xe2x80x94N(R5)(R6) or lower alkyl,
or is xe2x80x94N(R5)-phenyl, which is unsubstituted or substituted by lower alkoxy, or is
b) xe2x80x94(CH2)nxe2x80x94 five or six membered aromatic or non aromatic heterocycle, with the exception of the the piperazinyl group in case if n=0, which rings may be optionally substituted by 2-oxo-pyrrolidin, piperidinyl, phenyl, xe2x80x94(CH2)nOH, halogen, CF3, xe2x95x90O,
lower alkyl, cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nNH2, xe2x80x94(CH2)nCN, xe2x80x94C(O)O-lower alkyl, xe2x80x94CH2xe2x80x94Oxe2x80x94S(O)2CH3, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)xe2x80x94(CH2)n-lower alkoxy, xe2x80x94CH2xe2x80x94N(R6)C6H4F, xe2x80x94CH2xe2x80x94N(R6)C(O)O-lower alkyl,
xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94(CH2)nxe2x80x94O-lower alkyl, -or by tetrahydrofuran, substituted by
4-Cl-phenyl, or by piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl, or is
c) xe2x80x94N(R5)(CH2)n+1-phenyl, unsubstituted or substituted by lower alkoxy,
xe2x80x94O(CH2)n-phenyl, or
xe2x80x94N(R5)C(O)-phenyl, or is
d) xe2x80x94N(R5)(CH2)nxe2x80x94 5-or 6 membered aromatic or non aromatic heterocycle, unsubstituted or substituted by lower alkyl, xe2x80x94(CH2)nxe2x80x94 5-or 6 membered aromatic or nonaromatic heterocycle or is
e) xe2x80x94Oxe2x80x94(CH2)n-lower alkoxy, lower alkyl-lower alkoxy, xe2x80x94N(R5)(CH2)nN(R5)(R6), xe2x80x94(CH2)nOH, xe2x80x94(HCxe2x95x90CH)nC(O)O-lower alkyl, octahydro-quinoline, 3,4-dihydro-1H-isoquinoline, 2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or 1,4-dioxa-8-aza-spiro[4,5]decane.
X is O, S or two hydrogen atoms;
R5, R6 are independently from each other hydrogen or lower alkyl,
R7 is lower alkyl, lower alkoxy, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)O-benzyl, xe2x80x94C(O)O-lower alkyl,
xe2x80x94CH2)nNR5R6, pyridinyl, unsubstituted or substituted by lower alkyl, or is xe2x80x94CH2N(R5)xe2x80x94C(O)O-lower alkyl, xe2x80x94NHxe2x80x94C(phenyl)3, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, unsubstituted or substituted by lower alkyl;
n is 0, 1, 2, 3 or 4;
m is 0 or 1;
is 0, 1, 2, 3 or 4;
or pharmaceutically acceptable salts thereof.